The extreme dependence of the brain upon its circulation for substrates essential for the maintenance of its metabolic activity is well recognized. A cessation of the cerebral circulation for only a few minutes, as occurs in cardiac arrest, results in irreversible brain damage. The brain, for the most part, is an aerobic organ and its large oxygen demands probably account for its unusual susceptibility to circulatory disturbances.The oxygen consumed by the normal adult brain (3.5 cc. per 100 Gm. per min.) is extracted from approximately 800 cc. of blood passing through it each minute. The minimum blood flow requirements of the brain, i.e., the rate at which signs of cerebral ischemia become manifest, have not been accurately determined. Previous efforts to estimate the critical rate have been made both in animals (1) and in man (2) but the procedures utilized for the determination of cerebral blood flow were not sufficiently quantitative to warrant definite conclusions. In order to study this problem, cerebral hemodynamic and metabolic changes were determined before and during acute reductions in arterial pressure induced by drug administration and/or postural adjustments. MATERIALS AND METHODForty-four patients were studied. The subjects in whom hypotension was drug-induced were separated into the following four groups so that the influence of age and hypertension on the susceptibility of the brain to cerebral ischemia could be determined: Group 1, seven normotensive subjects under 50 years of age; Group 2, ten normotensive subjects over 60 years of age; Group 3, eight patients with essential hypertension; and Group 4, seven patients with malignant hypertension. In seven subjects, the mean arterial pressure was reduced significantly below normal but not to the extent of inducing signs of cerebral ischemia. Five patients with spontaneous postural hypotension were also studied.Control studies were obtained after the subject had been tilted (head up) 30 to 40 degrees for a period of at least 30 minutes. The subjects in the drug-induced hypotension group were then given a 1 per cent solution of hexamethonium 2 intravenously at a rate of 1 mg. of the ion per minute and carefully observed for signs of cerebral ischemia. In the subjects with spontaneous postural hypotension, control studies were done in the horizontal position, and the subjects were then tilted 30 degrees head up, and the experimental flow was done when they developed signs of cerebral ischemia.The manifestations of cerebral circulatory insufficiency were Father stereotyped and easily recognized. Sighing, yawning, staring, and confusion, i.e., the inability to follow simple commands, were the first indications of cerebral ischemia. When any of these signs appeared, the hexamethonium injection was promptly discontinued, and the second, or experimental flow was begun. A fairly steady state was maintained during the first few minutes making postural adjustments unnecessary. If during the experimental flow, the patient became either unresponsive or too al...

Further data are presented concerning the unusual hemodynamic effects of 1 -hiydraziniophthalazine. Previous observations demonstrating a marked increase in cardiac output in noimotensive subjects are confirmed in hypertensive patients. The splanchnic vascular bed is one of the sites of increased blood flow. The similarity between the hemodynamic effects of 1-bydr.azinophthalazine and pyirogens is pointed out and the pharmacologic basis for the clinically observed additive effects of 1-1yd)rdazinol)lpthalazine an(d hexamethonium is (liscusse(l. G ROSS and his co-workers, in animals, ' and Reubi, in man,2 were the first to demonstrate that 1-hydrazinophthalazine (Apresoline) produces a reduction of arterial pressure and simultaneously an increase in renal blood flow. Since then considerable attention has been directed toward the further elucidation of the hemodynamic effects of this agent. Moyer and his associates, working with dogs, noted a marked increase in cardiac output and decrease in total peripheral resistance following administration of 1-hydrazinophthalazine.3 This observation was confirmed in normal and hypertensive pregnant women by Assali and his co-workers using the ballistocardiographic method4 and in normal subjects by Wilkinson and his associates using the intra-

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Hexamethonium by subcutaneous injection in doses of 10 to 75 mg. of the ion every 8 or 12 hours produced significant reductions of arterial pressure after 50 to 100 mg. of C6 ion in normal subjects suggested that this compound produced nearly complete blockade of the sympathetic outflow to the foot'0 and was, therefore, considerably more potent than previously known vasodilator agents." The present communication outlines our experience to date with C6 in the treatment of hypertension. The dosages of hexamethonium given in this paper refer to the amount of C6 ion rather than of the salt hexamethonium dibromide. TIME-DOSE RELATIONSHIPSFollowing the intravenous administration of 5 to 50 mg. of C6 ion (9.6 to 96 mg. of hexamethonium dibromide) the cardiovascular effects of the drug appeared within two to three minutes and quickly reached a maximum within 10 minutes or less. These effects consisted of a reduction of blood pressure and increase of heart rate, both of variable degree, as well as a consistent marked postural hypotension. Following the larger doses there also was a marked increase of foot blood flow and digital skin temperature. The peak of these effects usually lasted 15 minutes after which there was a gradual waning over a period of 5 to 10 hours. The heart rate usually increased only-slightly and at times actually decreased.By the intramuscular and subcutaneous routes responses occurred at 15 to 30 minutes following injection and persisted for a period similar to that observed after intravenous administration.

By giving diazoxide intravenously and furosemide orally the diastolic blood pressure was kept under 110 mm Hg and the urinary output over 1 L/day for a 2-week period in 25 hypertensive patients with azotemia. During the first 2 weeks of treatment three patients died. Although the 40% decrease in mean arterial pressure in the remaining patients was associated with immediate improvement in the cardiovascular status, for example, clearing of congestive heart failure and papilledema, there was a 19% average increase in BUN and 17% average increase in serum creatinine values. Three months later, however, maintenance of the reduced arterial pressure was associated with average reductions of 24 mg/1100 ml in BUN and of 2.8 mg/100 ml in serum creatinine below control values. Each of the patients who remained on therapy continued to do well. Twenty-six months later six additional patients had died. In the remaining 16 patients the average mean arterial pressure was 117 mm Hg; papilledema had cleared; the average concentration of BUN was 22 mg/100 ml; the average serum creatinine was 1.8 mg/ 100 ml.

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23stimulating effect of BIZ is more marked in females onl high carbohydrate diets than in littermate sisters on dilets of like protein con-tent but with the calories provided by fat or a mixture of fat and carbohydrate.